Project Summary The molecular mechanisms controlling stem cell self-renewal, competition and differentiation hold great potential for advances in treating cancer, and in regenerative medicine and in stem cell-based therapies. Stem cells reside in specialized, quiescent microenvironments called niches that secrete short-range signals promoting the maintenance of resident stem cells. Much is known about what regulates the autonomous behaviors within each stem cell type. However, much less is known about the competitive behaviors of between stem cells. The Drosophila testis is one of the best characterized paradigms for investigating stem cell behavior. In this tissue, a single quiescent niche supports two stem cell populations: germline stem cells (GSCs), which give rise to sperm, and somatic cyst stem cells (CySCs), which produce cyst cells. Prior work has shown that GSCs compete with each other for limited space at the niche, but little is known about molecular mechanisms controlling this cooperativity. This proposal reveals the first mutation that endows a male GSC with the ability to out-compete its wild-type neighbors and colonize the testis stem cell niche. The preliminary data in this application show that a competitive GSC and its descendants in the Drosophila testis disadvantage their wild-type neighbors by altering the niche milieu. Additionally, the competitive GSCs remain immune to these alterations by upregulating adhesion factors. Sophisticated genetic techniques in Drosophila will be used to achieve the aims in this proposal. Aim 1 is focused on the transcriptional regulation of extracellular matrix factors in competitive GSCs. Aim 2 will test the model that competitive GSCs have increased adhesion, thus allowing them to remain in the niche while their wild-type neighbors differentiate. We envision this work will impact human reproductive biology and regenerative medicine.